From a population perspective, chronological age is arguably the most important biological trait in predicting age-related disease risks, mental and physical performance, and mortality [1]. The use of chronological age is limited, however, in explaining the large biological variation among individuals of a similar age. Biological age is a concept that attempts to quantify different aging states influenced by lifestyle, genetics, disease, and environment. Environmental and lifestyle choices such as smoking and diet also have clear implications with respect to age-associated diseases [2]. While epidemiological studies have succeeded in providing quantitative assessments of their impact on human longevity, advances in molecular biology now offer the ability to look beyond population questions of mortality, and to hone in on the specific effects of disease and other factors on aging within single organisms.
A quantitative model for aging based on genome-wide DNA methylation patterns by using measurements at 470,000 CpG markers from whole blood samples of a large cohort of human individuals spanning a wide age range has been developed [3]. This method is highly accurate at predicting age, and can also discriminate relevant factors in aging, including gender, genetic variants and disease [3, 4]. The model works in multiple tissues, suggesting the possibility of a common molecular clock, regulated in part by changes in the methylome. In addition, these methylation patterns are strongly correlated with cellular senescence and aging. Several genes were observed to become progressively more methylated with increasing chronological age. ELOVL2 (Elongation Of Very Long Chain Fatty Acids-Like 2), in particular, very reliably shows increased methylation as humans age, as revealed by the aging model [3].
ELOVL2 encodes a transmembrane protein involved in the synthesis of long (C22 and C24) ω3 and ω6 polyunsaturated fatty acids (VLC-PUFA) [5]. Specifically, ELOVL2 is capable of converting docosapentaenoic acid (DPA) (22:5n-3) to 24:5n-3, which is the precursor of 22:6n-3, docosahexaenoic acid (DHA) [6]. DHA is the major polyunsaturated fatty acid (PUFA) in the retina and brain. Its presence in photoreceptors promotes healthy retinal function and protects against damage from bright light and oxidative stress. Low ELOVL2 expression has been linked to low levels of DHA [7], which in turn has been associated with age-related macular degeneration (AMD), among a host of other retinal degenerative diseases [8]. In general, PUFAs are involved in crucial biological functions including energy production, modulation of inflammation, and maintenance of cell membrane integrity. It is therefore possible that ELOVL2 methylation plays a role in the aging process through the regulation of different biological pathways.
AMD is a degenerative disease of the macula, is the leading cause of blindness among the elderly in developed countries. It is a multifactorial disease involving genetic, environmental, and metabolic factors, and there is currently no cure or effective prevention for it. A number of genes have been identified as risk factors, but many are still unknown. As AMD progresses, the center of vision becomes blurred, and eventually blind spots can develop. AMD occurs in two forms, wet AMD and dry AMD. In dry AMD, which affects about 90% of AMD patients, the focal deposition of acellular, polymorphous debris, called drusen, are usually the first observed clinical hallmarks of the disease. ELOVL4, another fatty acid elongase involved in the synthesis of VLC-PUFAs, is implicated in Stargardt macular dystrophy, a juvenile form of macular degeneration causing vision loss [9, 10].
AMD has been associated with oxidative stress in the retina [11]. Oxidative stress can result in inflammation and contribute to the development of macrophage activation [12]. Oxidized phospholipids have been shown to be reliable markers of oxidative stress, and they initiate inflammation by binding to the retinal pigment epithelium (RPE) and macrophages, activating downstream inflammatory cascades [13]. Oxidation-modified proteins and lipids have also been found in drusen and Bruch's membrane [14]. Phosphatidylcholine, a phospholipid highly enriched in the retina, contains the head group phosphocholine. The oxidation epitope of phosphocholine can be recognized by a natural antibody to phosphocholine, TEPC-15 [15], and has been shown to colocalize with drusen in the human AMD eye [16]. HTRA1, one of the main proteins associated with AMD, is also found to colocalize with drusen in the AMD eye [17]. In addition, several components of the complement cascade, including C3 complement fragments, C5 and the membrane attack complex C5b-9 have been found within drusen [18].
New methods of treatment of age-related macular degeneration are needed.